An activatable polymeric nano-spy for reversing the progression of diabetic osteoporosis

Diabetic osteoporosis (DOP), a grievous complication of diabetes mellitus, is marked by accelerated bone loss and heightened fracture susceptibility, thereby necessitating early detection and therapeutic intervention. To address this unmet clinical need, we herein report a polymeric nano-spy (RAFP NP) that can activate its near-infrared (NIR) fluorescence and release therapeutic drug in response to specific early-stage stimuli within the DOP environment for the diagnosis and treatment of DOP. RAFP NPs are self-assembled from an integrin-targeted and reactive oxygen species (ROS)-responsive amphiphilic copolymer (PLGA-TK-cRGD) that encapsulates the near-infrared fluorochrome Cy5 and the anti-ferroptosis drug Fer-1. Such structural design allows RAFP NPs to actively target the DOP region through specific interaction with the overexpressed integrin αvβ3 receptors and undergo the elevated ROS to induce the cleavage of thioketal (TK) moiety. Subsequently, RAFP NPs decompose to release Cy5 for NIR fluorescence imaging of DOP, while concurrently releasing Fer-1 to suppress osteoblast ferroptosis, promote osteogenesis, and ultimately reverse DOP progression. This study provides a potential tactic to construct smart nanoprobes for the early detection and treatment of DOP.